Piperidine derivatives and their use as antagonists of tachykinins

ABSTRACT

The present invention relates to piperidine derivatives of formula (I):  
                 
wherein 
     R represents halogen or C 1-4  alkyl;    R 1  represents hydrogen or C 1-4  alkyl;    R 2  represents hydrogen, C 1-4  alkyl;    R 3  represents hydrogen, C 1-4  alkyl;    R 4  represents trifluoromethyl, C 1-4  alkyl, C 1-4  alkoxy, trifluoromethoxy or halogen;    R 5  represents hydrogen, C 1-4  alkyl, C 3-7  cycloalkyl, C(O)R 6  or S(O) 2 R 6 ;    R 6  represents C 1-4  alkyl or C 3-7  cycloalkyl; m is zero or an integer from 1 to 3; n is an integer from 1 to 3; p is an integer from 1 to 2;    X and Y are independently C(O) or CH 2 ; provided that i) X and Y are not both C(O) and    ii) when X and Y are both CH 2  and p is 1, R 5  is not hydrogen, C 1-4  alkyl or C(O)R 6 ; and pharmaceutically acceptable salts and solvates thereof, the process for their preparation and their use in the treatment of conditions mediated by tachykinins.

The present invention relates to C-aryl piperidine derivatives, toprocesses for their preparation, to pharmaceutical compositionscontaining them and to their medical use.

In particular the invention relates to novel compounds which are potentand specific antagonists of tachykinins, including substance P and otherneurokinins.

WO 99/37304 discloses inter alia some 2-aryl-1,4-disubstitutedpiperidine derivatives as factor Xa inhibitors. Such compounds areuseful as inhibitors of blood coagulation in mammalian species.

WO 97/16440 and WO 02/32867 disclose certain 2-aryl 1,4-disubstitutedpiperidine derivatives as NK1 antagonists.

However, in the above cited documents there is neither disclosure norsuggestion of any compound as claimed herein.

Thus, the present invention provides compounds of formula (I)

wherein

-   R represents halogen or C₁₋₄ alkyl;-   R₁ represents hydrogen or C₁₋₄ alkyl;-   R₂ represents hydrogen, C₁₋₄ alkyl;-   R₃ represents hydrogen, C₁₋₄ alkyl;-   R₄ represents trifluoromethyl, C₁₋₄ alkyl, C₁₋₄ alkoxy,    trifluoromethoxy or halogen;-   R₅ represents hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C(O)R₆ or    S(O)₂R₆;-   R₆ represents C₁₋₄ alkyl or C₃₋₇ cycloalkyl;-   m is zero or an integer from 1 to 3;-   n is an integer from 1 to 3;-   p is an integer from 1 to 2;-   X and Y are independently C(O) or CH₂;    provided that-   i) X and Y are not both C(O) and-   ii) when X and Y are both CH₂ and p is 1, R₅ is not hydrogen, C₁₋₄    alkyl or C(O)R₆;    and pharmaceutically acceptable salts and solvates thereof.

A further embodiment of the invention provides compounds of formula (I)and pharmaceutically acceptable salts and solvates thereof, wherein

-   R represents halogen or C₁₋₄ alkyl;-   R₁ represents C₁₋₄ alkyl;-   R₂ represents hydrogen or C₁₋₄ alkyl;-   R₃ represents hydrogen, or C₁₋₄ alkyl;-   R₄ represents trifluoromethyl, C₁₋₄ alkyl, C₁₋₄ alkoxy,    trifluoromethoxy or halogen;-   R₅ represents hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or S(O)₂R₆;-   R₆ represents C₁₋₄ alkyl or C₃₋₇ cycloalkyl;-   m is zero or an integer from 1 to 3;-   n is an integer from 1 to 3;-   p is an integer from 1 to 2;-   X and Y are independently C(O) or CH₂;    provided that-   i) X and Y are not both C(O) and-   ii) when X and Y are both CH₂, R₅ is not hydrogen or C₁₋₄ alkyl;    and pharmaceutically acceptable salts and solvates thereof.

Suitable pharmaceutically acceptable salts of the compounds of generalformula (I) include acid addition salts formed with pharmaceuticallyacceptable organic or inorganic acids, for example hydrochlorides,hydrobromides, sulphates, alkyl- or arylsulphonates (e.g.methanesulphonates or p-toluenesulphonates), phosphates, acetates,citrates, succinates, tartrates, fumarates and maleates.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention includeboth compounds of formula (I) and their pharmaceutically acceptable acidaddition salts together with pharmaceutically acceptable solvates.

Suitable pharmaceutical acceptable salts of the compounds of generalformula (I) may be obtained in a crystalline form and/or in an amorphousform or as a mixture thereof.

It will be appreciated by those skilled in the art that the compounds offormula (I) contain at least two chiral centres (namely the carbon atomsshown as * in formula (I)) and these may be represented by the formulae(1a, 1b, 1c and 1d).

The wedge shaped bond indicates that the bond is above the plane of thepaper and is referred to as β configuration. The broken bond indicatesthat the bond is below the plane of the paper and is in the αconfiguration.

In general, in the specific compounds named below the β configuration atthe 2 position of piperidine ring corresponds to the R configuration andthe β configuration at the 4 position of piperidine ring corresponds tothe S configuration. The a configuration at the 2 position of piperidinering corresponds to the S configuration and the a configuration at the 4position of piperidine ring corresponds to the R configuration. Theassignment of the R or S configuration at the 2 and the 4 positions hasbeen made according to the rules of Cahn, Ingold and Prelog, Experientia1956,12, 81.

Further asymmetric carbon atoms are possible in the compound of formula(I). Thus, when R₂ and R₃ are not the same group, the compounds offormula (I) possess at least four asymmetric carbon atoms.

It is to be understood that all stereoisomeric forms, including allenantiomers, diastereoisomers and all mixtures thereof, includingracemates, are encompassed within the scope of the present invention andthe reference to compounds of formula (I) includes all stereoisomericforms unless otherwise stated.

Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

The term C₁₋₄ alkyl as used herein as a group or a part of the grouprefers to a straight or branched alkyl group containing from 1 to 4carbon atoms; examples of such groups include methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl or tert butyl.

The term halogen refers to a fluorine, chlorine, bromine or iodine atom.

The term C₃₋₇ cycloalkyl group means a non aromatic monocyclichydrocarbon ring of 3 to 7 carbon atoms such as, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A preferred group of compounds of formula (I) are those in which thecarbon atom at the 2-position of piperidine ring is in the βconfiguration.

When R represents halogen this is suitably chlorine or more preferablyfluorine or when R is C₁₋₄ alkyl this is suitably methyl or ethylwherein m is zero or an integer from 1 to 2.

Suitable values for R₂ or R₃ include hydrogen, a methyl, an ethyl or apropyl group.

R is preferably a halogen (e.g. fluorine) and/or a C₁₋₄ alkyl (e.g.methyl) group and m is preferably zero or an integer from 1 to 2.

R₁ is preferably a methyl group.

R₂ is preferably a hydrogen atom or a methyl group.

R₃ is preferably a hydrogen atom or a methyl group.

R₄ is preferably a trifluoromethyl group or halogen (i.e chlorine).

R₅ is preferably hydrogen, metyl, cyclopropyl, C(O)CH₃ or S(O)₂CH₃.

p is preferably 1.

A preferred class of compounds of formula (I) is that wherein each R isindependently a halogen (e.g. fluorine) or a C₁₋₄ alkyl (e.g. methyl)group, wherein m is 0, 1 or 2. More preferably m is 1 or 2. Within thisclass those wherein R is at the 2 and/or 4 position in the phenyl ringare particularly preferred.

Compounds of formula (I), wherein n is 2, represent a preferred class ofcompounds and within this class the groups R₄ are preferably at the 3and 5 position in the phenyl ring.

A further preferred class of compounds of formula (I) is that wherein

-   R is fluorine and/or methyl;-   R₁ is preferably a methyl group;-   R₂ is preferably a hydrogen atom or a methyl group;-   R₃ is preferably a hydrogen atom or a methyl group;-   R₄ is trifluoromethyl;-   R₅ is preferably hydrogen, metyl, cyclopropyl, C(O)CH₃ or S(O)₂CH₃;-   m is 1 or 2;-   n is 2;-   p is 1.

Preferred compounds according to the invention are:

-   2-(R)-(4-Fluoro-2-metyl-phenyl)-4-(R)-(3-oxo-piperazin-1-yl-)-piperidine-1-carboxylic    acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(3-oxo-piperazin-1-yl-)-piperidine-1-carboxylic    acid,-   (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(4-methyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylic    acid, 1-(3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-methyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylic    acid, 1-(3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-methyl-3-oxo-piperazin-1-yl)-piperidine-1-carboxylic    acid, [1 (R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(2-oxo-piperazin-1-yl)-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)methylamide;-   214-Fluoro-2-methyl-phenyl)-4-(S    2-oxo-piperazin-1-yl)-piperidine-1-carboxylic acid,-   (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(4-Fluoro-2-methyl-phenyl)-4-(S)₂-oxo-piperazin-1-yl)-piperidine-1-carboxylic    acid,-   (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4(S)-(2-oxo-4-methyl-piperazin-1-yl)-piperidine-1-carboxylic    acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(R)₄-Fluoro-2-methyl-phenyl)-4-(S)-(4-methyl-2-oxo-piperazin-1-yl)piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-methyl-2-oxo-piperazin-1-yl)-piperidine-1-carboxilic    acid, [1-(R)^(3,5)-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(4-cyclopropyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylic    acid, 1-(3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-cyclopropyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylic    acid, 1-(3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)4-(S)-(1-methanesulfonyl-piperazin-1-yl)-piperidine-1-carboxylic    acid, 1-(3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(R)-(4-Fluoro-2-methyl-phenyl)₄S)-(1-methanesulfonyl-piperazin-1-yl)-piperidine-1-carboxylic    acid, 1-[(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;    and pharmaceutically acceptable salts and solvates thereof.

The compounds of the invention are antagonists of tachykinins, includingsubstance P and other neurokinins, both in vitro and in vivo and arethus of use in the treatment of conditions mediated by tachykinins,including substance P and other neurokinins.

Tachykinins are a family of peptides that share a commoncarboxyl-terminal sequence (Phe-X-Gly-Leu-Met-NH2). They are activelyinvolved in the physiology of both lower and advanced lifeforms. Inmammalian lifeforms, the main tachykinins are substance P (SP),Neurokinin A (NKA) and Neurokinin B (NKB) which act as neurotransmittersand neuromodulators. Mammalian tachykinins may contribute to thepathophysiology of a number of human diseases.

Three types of tachykinins receptors have been identified, namelyNK1(SP-preferring), NK2 (NKA-preferring) and NK3 (NKB-preferring) whichare widely distributed throughout the central nervous (CNS) andperipheral nervous system.

Particularly, the compounds of the invention are antagonists of the NK1receptor.

By virtue of their efficacy as tachykinins receptor (expecially NK1receptor) antagonists, the compounds of the present invention areparticularly useful for the treatment of CNS disorders and psychoticdisorders, in particular in the treatment or prevention of depressivestates and/or in the treatment of anxiety.

NK₁-receptor binding affinity has been determined in vitro by measuringthe compounds' ability to displace [3H]-substance P (SP) fromrecombinant human NK₁ receptor expressed in Chinese Hamster Ovary (CHO)cell membranes and from gerbil and marmoset brain cortex homogenates.

Membrane preparation from hNK1-CHO cells were performed essentially asdescribed by Beattie et al. (Br. J. Pharmacol, 116:3149-3157, 1995).

hNK1-CHO cells were harvested in phosphate buffered saline (PBS)containing 5 mM EDTA and centrifuged at 913 g for 8 min at 4° C. Cellswere then re-suspended in 10 volumes of membrane-preparation buffer(HBEPES 50 mM, pH 7.4, containing 0.1 mM leupeptin, 40 μg/ml bacitracin,1 mM EDTA, 1 mM Pefabloc and 21M pepstatin A) and homogenised. Thesuspension was centrifuged at 48,000 g for 20 minutes at 4° C. The finalpellet was re-suspended in 10 volumes of membrane preparation buffer andre-homogenised. Suspensions of membrane were then frozen at −80° C.until required.

The assay volume of 200 μl consisted of 211 of DMSO or increasingconcentrations of test compound dissolved in DMSO (1 pM-1 μM finalconcentration), 100 μl of [3H]-SP (0.5 nM final concentration), and 100μl of membrane suspension (8 μg of protein per well) in incubationbuffer (containing 50 mM HEPES, pH 7.4, 3 mM MnCl2, and 0.02% BSA). Theincubation was carried out at room temperature for 40 min. Non-specificbinding was defined by the addition of cold SP (1 μM). The reaction wasstopped by rapid filtration. Filters were washed 5 times with 200 μl ofice-cold 0.9% w/v NaCl, and radioactivity was counted in a microplatescintillation counter. In each experiment, every concentration ofdisplacer was tested in duplicate.

Mongolian gerbil (60 g, Charles River) and common marmoset (Callithrixjacchus, 300-400 g, GSK colony, Verona, Italy) brain cortex homogenateswere prepared as follows: fresh tissues were weighed, crumbled andhomogenised in 10 volumes of membrane-preparation buffer. The homogenatewas then centrifuged at 48,000 g for 20 minutes, and the pellet waswashed once more by resuspension in 10 volumes of membrane preparationbuffer and centrifugation at 48,000 g for 20 minutes. The final pelletwas re-suspended in 7-10 volumes of membrane preparation buffer andsubdivided in aliquots frozen at −80° C. until use.

The assay volume of 400 μl consisted of 100 μL of incubation buffer(containing 50 mM HEPES, pH 7.4, 3 mM MnCl2, and 0.02% BSA), 4 μl ofDMSO or increasing concentrations of test compound dissolved in DMSO (1pM-1 μM final concentration), 100 μl of [3H)-SP (0.5 nM-0.8 nM finalconcentration) in incubation buffer and 200 μl of membrane suspension(0.6 mg protein for gerbil, and 0.8 mg protein for marmoset) inincubation buffer containing 2 μg/ml leupeptin, 20 μg/ml bacitracin and0.5 μM phosphoramidon. The incubation proceeded at room temperature for60 min. Non-specific binding was defined by the addition of cold SP (1μM). The reaction was stopped by rapid filtration. Filters were washed 3times with 1 ml ice cold wash buffer (containing 50 mM HEPES, pH 7.4,and 3 mM MnCl2), and radioactivity was counted in a liquid scintillationcounter.

The potency of test compounds to inhibit SP or GR73632-induced increaseof [Ca2+]i in hNK1/CHO cells was determined in functional experiments byusing FLIPR (fluorimetric imaging plate reader) technology.

hNK1/CHO cells were seeded at a density of 60,000 cells per well andcultured overnight in Ham's F-12 medium supplemented with 10% (v/v)heat-inactivated foetal bovine serum and 2 mM glutamine. The cells werethen incubated for the labelling in the culture medium containing thefluorescent calcium indicator Fluo-4 AM (2 μM), the organic anionstransport blocker probenecid (5 mM), and HEPES (20 mM) for 30 min in ahumidified atmosphere of 5% CO₂. After washing with Hanks' BalancedSalts Solution (HBSS) containing 20 mM HEPES and 2.5 mM probenecid, thecells were incubated for 60 min at 37 C in wash buffer containing 0.02%BSA either in the absence (control) or in the presence of testcompounds. The plates were then placed into a FLIPR to monitor cellfluorescence (ex=488 nm, em=510-570 nm) before and after the addition ofdifferent concentrations of SP or GR73632 in assay buffer. Experimentswere carried out by using a laser setting of 1.0 W and a 0.4 sec chargecoupled device (CCD) camera shutter speed.

Compounds of the invention have also been found to exhibit anxiolyticactivity in conventional tests. For example in marmoset human threattest (Costall et al., 1988).

The action of the compounds of the invention at the NK₁ receptor may bedetermined by using conventional tests. Thus, the ability to penetratethe central nervous system and to bind at the NK₁ receptor wasdemonstrated in vivo by their inhibitory effect on the change in thebehaviour induced by intracerebroventricular applied substance P in thegerbil, according to the gerbil foot tapping model as described byRupniak & Williams, Eur. J. of Pharmacol., 265, 179-183, 1994.

Compounds of the invention are useful in the treatment of CNS disordersand psychotic disorders, in particular in the treatment or prevention ofdepressive states and/or in the treatment of anxiety as defined in, butnot restricted to, Diagnostic Statistical of Mental Disorder (DSM) IVedition edit by American Psychiatric Association and InternationalClassification Diseases 10th revision (ICD10).

Thus, for example, depressive states include Major Depressive Disorders(MDD), including bipolar depression, unipolar depression, single orrecurrent major depressive episodes, recurrent brief depression, with orwithout psychotic features, catatonic features, melancholic featuresincluding anorexia, weight loss, atypical features, anxious depression,cyclothymic or postpartum onset.

Other mood disorders encompassed within the term major depressivedisorders include dysthymic disorders with early or late onset and withor without atypical features, neurotic depression, post-traumatic stressdisorders and social phobia; dementia of the Alzheimer's type, withearly or late onset, with depressed mood; vascular dementia withdepressed mood; mood disorders induced by alcohol, amphetamines,cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives,hypnotics, anxiolytics and other substances; schizoaffective disorder ofthe depressed type; and adjustment disorder with depressed mood. Majordepressive disorders may also result from a general medical conditionincluding, but not limited to, myocardial infarction, diabetes,miscarriage or abortion, etc.

The term anxiety includes anxiety disorders, such as panic disorderswith or without agoraphobia, agoraphobia, phobias, for example, socialphobias or agoraphobia, obsessive-compulsive disorder, stress disordersincluding post-traumatic stress disorders, generalised anxietydisorders, acute stress disorders and mixed anxiety-depressiondisorders.

Compounds of the invention are useful as analgesics. In particular, theyare useful in the treatment of traumatic pain such as postoperativepain; traumatic avulsion pain such as brachial plexus; chronic pain suchas arthritic pain such as occurring in osteo-, rheumatoid or psoriaticarthritis; neuropathic pain such as post-herpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia,peripheral neuropathy, diabetic neuropathy, chemotherapy-inducedneuropathy, AIDS related neuropathy, occipital neuralgia, geniculateneuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,phantom limb pain; various forms of headache such as migraine, acute orchronic tension headache, temporomandibular pain, maxillary sinus pain,cluster headache; odontalgia; cancer pain; pain of visceral origin;gastrointestinal pain; nerve entrapment pain; sports injury pain;dysmennorrhoea; menstrual pain; meningitis; arachnoiditis;musculoskeletal pain; low back pain e.g. spinal stenosis; prolapseddisc; sciatica; angina; ankylosing spondyolitis; gout; burns; scar pain;itch and thalamic pain such as post stroke thalamic pain.

Compounds of the invention are also useful in the treatment of sleepdisorders including dysomnia, insomnia, sleep apnea, narcolepsy, andcircadian ritmic disorders.

Compounds of the invention are also useful in the treatment orprevention of the cognitive disorders. Cognitive disorders includedementia, amnestic disorders and cognitive disorders not otherwisespecified.

Furthermore, compounds of the invention are also useful as memory and/orcognition enhancers in healthy humans with no cognitive and/or memorydeficit.

Compounds of the invention are also useful in the treatment of toleranceto and dependence on a number of substances. For example, they areuseful in the treatment of dependence on nicotine, alcohol, caffeine,phencyclidine (phencyclidine like compounds) or in the treatment oftolerance to and dependence on opiates (e.g. cannabis, heroin, morphine)or benzodiazepines; in the treatment of addiction to cocaine, sedativeipnotic, amphetamine or amphetamine-related drugs (e.g.dextroamphetamine, methylamphetamine) or a combination thereof.

Compounds of the invention are also useful as anti-inflammatory agents.In particular, they are useful in the treatment of inflammation inasthma, influenza, chronic bronchitis and rheumatoid arthritis; in thetreatment of inflammatory diseases of the gastrointestinal tract such asCrohn's disease, ulcerative colitis, inflammatory bowel disease andnon-steroidal anti-inflammatory drug induced damage; inflammatorydiseases of the skin such as herpes and eczema; inflammatory diseases ofthe bladder such as cystitis and urge incontinence; and eye and dentalinflammation.

Compounds of the invention are also useful in the treatment of allergicdisorders, in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis.

Compounds of the invention are also useful in the treatment orprevention of schizophrenic disorders including paranoid schizophrenia,disorganised schizophrenia, catatonic schizophrenia, undifferentiatedschizophrenia, residual schizophrenia.

Compounds of the invention are also useful in the treatment of emesis,i.e. nausea, retching and vomiting. Emesis includes acute emesis,delayed emesis and anticipatory emesis. The compounds of the inventionare useful in the treatment of emesis however induced. For example,emesis may be induced by drugs such as cancer chemotherapeutic agentssuch as alkylating agents, e.g. cyclophosphamide, carmustine, lomustineand chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin,mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine,methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide,vinblastine and vincristine; and others such as cisplatin, dacarbazine,procarbazine and hydroxyurea; and combinations thereof; radiationsickness; radiation therapy, e.g. irradiation of the thorax or abdomen,such as in the treatment of cancer; poisons; toxins such as toxinscaused by metabolic disorders or by infection, e.g. gastritis, orreleased during bacterial or viral gastrointestinal infection;pregnancy; vestibular disorders, such as motion sickness, vertigo,dizziness and Meniere's disease; post-operative sickness;gastrointestinal obstruction; reduced gastrointestinal motility;visceral pain, e.g. myocardial infarction or peritonitis; migraine;increased intercranial pressure; decreased intercranial pressure (e.g.altitude sickness); opioid analgesics, such as morphine; andgastro-oesophageal reflux disease (GERD) such as erosive GERD andsymptomatic GERD or non erosive GERD, acid indigestion, over-indulgenceof food or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn, dyspepsia and functional dyspepsia.

Compounds of the invention are also useful in the treatment ofgastrointestinal disorders such as irritable bowel syndrome,gastro-oesophageal reflux disease (GERD) such as erosive GERD andsymptomatic GERD or non erosive GERD, acid indigestion, over-indulgenceof food or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn, dyspepsia and functional dyspepsia (such asulcer-like dyspepsia, dysmotility-like dyspepsia and unspecifieddyspepsia) chronic constipation; skin disorders such as psoriasis,pruritis and sunburn; vasospastic diseases such as angina, vascularheadache and Reynaud's disease; cerebral ischeamia such as cerebralvasospasm following subarachnoid haemorrhage; fibrosing and collagendiseases such as scleroderma and eosinophilic fascioliasis; disordersrelated to immune enhancement or suppression such as systemic lupuserythematosus and rheumatic diseases such as fibrositis; and cough.

The compounds of the invention are also useful in premenstrual dysphoricdisorder (PMDD), in chronic fatigue syndrome and Multiple sclerosis.

Compounds of the invention have been found to exhibit anxiolytic andantidepressant activity in conventional tests. For example, in Guineapig pups separation-induced vocalisations (Molewijk et al., 1996).

Compounds of the invention are also useful in the treatment ofconvulsions and epilepsy.

Compounds of the invention may be administered in combination with otheractive substances such as 5HT3 antagonists, serotonin agonists,selective serotonin re-uptake inhibitors (SSRI), noradrenaline re-uptakeinhibitors (SNRI), tricyclic antidepressants or dopaminergicantidepressants.

Suitable S51H antagonists which may be used in combination with thecompounds of the inventions include for example ondansetron, granisetronand metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbineand metoclopramide.

Suitable SSRI which may be used in combination with the compounds of theinvention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline and zimeldine.

Suitable SNRI which may be used in combination with the compounds of theinvention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention include imipramine, amitriptiline,chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combinationwith a compound of the invention include bupropion and amineptine.

It will be appreciated that the compounds of the combination may beadministered simultaneously (either in the same or differentpharmaceutical formulations) or sequentially.

The invention therefore provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in therapy,in particular in human medicine.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof in the preparation of a medicament for use in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins, comprising administration of an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.Compounds of formula (I) may be administered as the raw chemical but theactive ingredient is preferably presented as a pharmaceuticalformulation.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or apharmaceutically acceptable salt thereof and formulated foradministration by any convenient route. Such compositions are preferablyin a form adapted for use in medicine, in particular human medicine, andcan conveniently be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers or excipients.

Thus, compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), depot or rectaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

A proposed dose of the compounds of the invention is 1 to about 1000 mgper day. It will be appreciated that it may be necessary to make routinevariations to the dosage, depending on the age and condition of thepatient and the precise dosage will be ultimately at the discretion ofthe attendant physician or veterinarian. The dosage will also depend onthe route of administration and the particular compound selected.

Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined hereinafter. In the followingdescription, the groups R, R₁, R₂, R₃, R₄, R₅ R_(6,) m, n and p, havethe meaning as previously defined for compounds of formula (I) unlessotherwise stated.

Compounds of formula (I), wherein X is CH₂ or C(O) and Y is CH₂, may beprepared by reductive N-alkylation of a compound of formula (II),

with a piperazine derivative (III) in an aprotic solvent such asdichloroethane and in the presence of a suitable metal reducing agentsuch as sodium borohydride or sodium triacetoxyborohydride.

Compounds of formula (II) may be prepared by treating compounds offormula (IV)

with triphosgene in an aprotic solvent such as dichloromethane and inthe presence of an organic base such triethylamine to form theintermediate carbonyl chloride compound (V) which may be isolated ifrequired, followed by reaction of compound (V) with the amine compound(VI)

The reaction conveniently takes place in an aprotic solvent such as ahydrocarbon, a halohydrocarbon such as dichloromethane or an ether suchas tetrahydrofuran optionally in the presence of a base such as atertiary amine e.g. diisopropylethylamine.

Compounds of formula (I), wherein Y is C(O), may be prepared bycyclisation of a compound of formula (VII), wherein P is a nitrogenprotecting group, L is a suitable leaving group (i.e chlorine orbromine),

followed by removal of any protecting group.

The cyclisation reaction takes place in an aprotic solvent such asdichloromethane at a temperature ranging from 0° to 25° C.

Suitable nitrogen protecting reagents are those described by T. W.Greene and P. G. M Wuts in Protective Groups in Organic Synthesis 2^(nd)ed., John Wiley & Son, Inc 1991, which is incorporated by reference. Anexample of a suitable nitrogen protecting group is t-butyloxycarbonyl.

Where it is desired to isolate a compound of formula (I) as a salt, forexample a pharmaceutically acceptable salt, this may be achieved byreacting the compound of formula (I) in the form of the free base withan appropriate amount of suitable acid and in a suitable solvent such asan alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) oran ether (e.g. diethyl ether or tetrahydrofuran).

Pharmaceutically acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts of the compounds offormula (I) using conventional methods.

Compounds of formula (IV), (V) and (VI) may be prepared by analogousmethods to those used for known compounds.

Compound of formula (I) may be converted into another compound offormula (I). Thus, compounds of formula (I) wherein R₅ is C(O)R₆ orS(O)₂R₆ can be prepared by reaction of a compound of formula (I) whereinR₅ is hydrogen with L-C(O)R₆ or L-S(O)₂R₆, wherein L is a suitableleaving group (such as chlorine or bromine).

The compounds of formula (I) may readily be isolated in association withsolvent molecules by crystallisation from or evaporation of anappropriate solvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods.

Thus, for example, specific enantiomers of the compounds of formula (I)may be obtained from the corresponding enantiomeric mixture of acompound of formula (I) using chiral HPLC procedure.

Alternatively, enantiomers of a compound of general formula (I) may besynthesised from the appropriate optically active intermediates usingany of the general processes described herein.

Thus, for example the required enantiomer may be prepared by thecorresponding chiral piperidin-4-one of formula (IV) using the processdescribed above for preparing compounds of formula (I) from compounds(IV), followed by separation of the diastereomeric mixture of a compoundof formula (I) using conventional procedure.

The chiral compounds (IV) may be prepared from the corresponding racemiccompound (IV) using conventional procedures such as salt formation witha suitable optically active acid, separating the resultantdiastereoisomeric salts by conventional means e.g. chromatography andcrystallisation followed by hydrolysis of the diastereoisomeric salts.

A suitable optically active acid for use in the process is L(+)mandelicacid.

In a further embodiment of the invention the chiral compound (IV) may beprepared using Comins reaction as described in Journal American ChemicalSociety 1994,116, 47194728, followed by reduction of 2,3dihydro-1H-pyridin-4-one derivative to piperidinone derivative. Thereduction may be effected using hydrogen and metal catalyst e.g.palladium on a suitable support e.g. carbon or alumina. The reaction iscarried out in a solvent such as ester e.g. ethyl acetate.

In a further embodiment of the invention the enantiomers of the compoundof formula (I) may be prepared by reaction of a chiral amine (VI) usingany of the processes described above for preparing compounds of formula(I) from amine (V).

The chiral amine (III) may be prepared from the corresponding racemicamine (III) using any conventional procedures such as salt formationwith a suitable optically active acid.

The invention is further illustrated by the following Intermediates andExamples which are not intended as a limitation of the invention.

In the Intermediates and Examples unless otherwise stated:

Melting points (m.p.) were determined on a a Büchi 530 melting pointapparatus and are uncorrected. All temperatures refers to IC. Infraredspectra were measured on a FT-IR instrument. ¹H-NMR spectra wererecorded on Varian instruments at 400 or 500 MHz, chemical shifts arereported in ppm (δ) using the residual solvent line as internalstandard. The signals are assigned as singlets (s), doublets (d),doublets of doublets (dd), triplets (t), quartets (q) or multiplets (m).Mass spectra were taken on a VG Quattro mass spectrometer. Flash columnchromatography was carried out over silica gel (Merck AG Darmstaadt,Germany). Optical rotations were determined at 20° C. with a JascoDIP360 instrument (l=10 cm, cell volume=1 mL, A=589 nm). The followingabbreviations are used in the text: AcOEt=ethyl acetate, CH=cyclohexane,DCM=dichloromethane, Et₂O=diethyl ether, DMF=N,N′-dimethylformamide,DIPEA=N,N-diisopropylethylamine, MeOH=methanol, TEA=triethylamine,TFA=trifluoroacetic acid, THF=tetaahydrofuran. T.l.c. refers to thinlayer chromatography on 0.25 mm silica plates (60F-254 Merck) and driedrefers to solution dried over anhydrous sodium sulphate; r.t. (RT)refers to room temperature.

Intermediate 1

1-(Benzyloxycarbonyl)-2-(4-fluoro-2-methyl-phenyl)-2,3-dihydro-4-pyridone

A small amount of iodine was added to a suspension of magnesium turnings(13.2 g) in dry THF (300 mL), at r.t., under a nitrogen atmosphere, thenthe mixture was vigorously refluxed for 20 minutes. To this suspension,a 15% of a solution of 2-bromo-5-fluoro-toluene (52.5 mL) in anhydrousTHF (300 mL) was added. The suspension was heated under vigorous refluxuntil the brown colour disappeared. The remaining part of the bromidesolution was added drop-wise over 1 hour to the refluxing suspensionwhich was then stirred for a further 1 hour. This solution of Grignardreagent was then added drop-wise to the pyridinium salt obtained frombenzyl chloroformate (48.7 mL) and 4-methoxypyridine (25 mL) in dry THF(900 mL) at −23° C.

The obtained solution was stirred 1 hour at −20° C. then it was warmedup to 20° C., a 10% hydrochloric acid solution (560 mL) was added andthe aqueous layer was extracted with AcOEt (2×750 mL).

The combined organic extracts were washed with 5% sodium hydrogencarbonate solution (600 mL) and brine (600 mL) then partiallyconcentrated in vacuo.

CH (400 mL) was added drop-wise over 1 hour at 20° C. and the resultingmixture was stirred 30 minutes and then filtered to give the titlecompound as a white solid (66 g).

IR (nujol, cm⁻¹): 1726 and 1655 (C═O), 1608 (C═C).

NMR (d₆-DMSO): δ (ppm) 8.19 (d, 1H); 7.31-7.18 (m, 5H); 7.08 (m, 2H);6.94 (dt, 1H); 5.77 (d, 1H); 5.36 (d, 1H); 5.16 (2d, 2H); 3.26 (dd, 1H);2.32 (d, 1H); 2.26 (s, 3H).

MS (ES/+): m/z=340 [MH]⁺.

Intermediate 2

2-(4-Fluoro-2-methyl-phenyl)-piperidine-4-one

Method A

4-Fluoro-2-methyl-benzaldehyde (4 g) was added to a solution of4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) andthe solution was stirred at r.t. under a nitrogen atmosphere. After 1hour the mixture was heated at reflux for 16 hours and then allowed tocool to r.t. This solution was slowly added to a refluxing solution ofp-toluensulphonic acid (10.6 g) in dry benzene (50 mL) previouslyrefluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours thecrude solution was cooled and made basic with a saturated potassiumcarbonate solution and taken up with AcOEt (50 mL). The aqueous phasewas extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layerwas dried and concentrated in vacuo to a yellow thick oil as residue(7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6Nhydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours.The solution was basified with solid potassium carbonate and extractedwith DCM (5×50 mL). The combined organic phases were washed with brine(50 mL), dried and concentrated in vacuo to give the title compound (2.5g) as a thick yellow oil.

Method B

L-selectride (1M solution in dry THF, 210 mL) was added drop-wise, over80 minutes, to a solution of intermediate 1 (50 g) in dry THF (1065 mL)previously cooled to −72° C. under a nitrogen atmosphere. After 45minutes, 2% sodium hydrogen carbonate solution (994 mL) was addeddrop-wise and the solution was extracted with AcOEt (3×994 mL). Thecombined organic phases were washed with water (284 mL) and brine (568mL). The organic phase was dried and concentrated in vacuo to get1-benzyloxycarbonyl-2-(4-fluoro-2-methyl-phenyl) piperidine-4-one as apale yellow thick oil (94 g) which was used as a crude.

This material (94 g) was dissolved in AcOEt (710 mL), then 10% Pd/C(30.5 g) was added under a nitrogen atmosphere. The slurry washydrogenated at 1 atmosphere for 30 minutes. The mixture was filteredthrough Celite and the organic phase was concentrated in vacuo to givethe crude 2-(4-fluoro-2-methyl-phenyl)piperidine-4-one as a yellow oil.This material was dissolved in AcOEt (518 mL) at r.t. and racemiccamphorsulphonic acid (48.3 g) was added. The mixture was stirred at r.tfor 18 hours, then the solid was filtered off, washed with AcOEt (2×50mL) and dried in vacuo for 18 hours to give2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one, 10-camphorsulfonic acidsalt as a pale yellow solid (68.5 g). (M.p.: 167-169° C.—NMR (d₆-DMSO):δ (ppm) 9.43 (bs, 1H); 9.23 (bs, 1H); 7.66 (dd, 1H); 7.19 (m, 2H); 4.97(bd, 1H); 3.6 (m, 2H); 2.87 (m, 3H); 2.66 (m, 1H); 2.53 (m, 2H); 2.37(s+d, 4H); 2.22 (m, 1H); 1.93 (t, 1H); 1.8 (m, 2H); 1.26 (m, 2H); 1.03(s, 3H); 0.73 (s, 3H).

This material (68.5 g) was suspended in AcOEt (480 mL) and stirred witha saturated sodium hydrogen carbonate (274 mL). The organic layer wasseparated and washed with further water (274 mL). The organic phase wasdried and concentrated in vacuo to give the title compound (31 g) as ayellow-orange oil.

NMR (d₆-DMSO): δ (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27(m, 1H); 2.82 (dt, 1H); 2.72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29(s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H).

MS (ES/+): m/z=208 [M+.

Intermediate 3

2-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic Acid(3.5-bis-trifluoromethyl-benzyl)-methylamide

A solution of triphosgene (1.43 g) dissolved in dry DCM (10 mL) wasadded to a solution of intermediate 2 (2.5 g) and DIPEA (8.4 mL) in dryDCM (20 mL) previously cooled to 0° C. under a nitrogen atmosphere. Thesolution was stirred at 0° C. for 2 hours, then(3,5-bis-trifluoromethyl-benzyl)-methylamine hydrochloride (5.63 g) andDIPEA (3.34 mL) were added. The mixture was stirred under nitrogen atr.t. for 14 hours. The mixture was taken up with AcOEt (50 mL), washedwith cold 1N hydrochloric acid solution (3×20 mL) and brine (10 mL). Theorganic layer was dried and concentrated in vacuo to a residue which waspurified by flash chromatography (AcOEt/CH 3:7) to give the titlecompound as a white foam (3.85 g).

IR (nujol, cm⁻¹): 1721 and 1641 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.25 (dd, 1H); 6.97(dd, 1H); 6.90 (dt, 1H); 5.22 (t, 1H); 4.59 (d, 1H); 4.43 (d, 1H);3.63-3.49 (m, 2H); 2.79 (s, 3H); 2.69 (m, 2H); 2.49 (m, 2H); 2.26 (s,3H).

MS (ES/+): m/z=491 [MH]⁺.

Intermediate 4

2-(R)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid[1-(R)-3,5-bis-trifluoromethyl-phenyl)ethyl]-methylamide (4a) and2-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic Acid[1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (4b)

Method A:

A solution of triphosgene (147 mg) dissolved in dry DCM (5 mL) was addeddrop-wise to a solution of intermediate 2 (250 mg) and DIPEA (860 μL) indry DCM (15 mL) previously cooled to 0° C. under a nitrogen atmosphere.After 2 hours, [1-(R)-3,5-bis-trifluoromethyl-phenyl)ethyl]-methylaminehydrochloride (503 mg) and DIPEA (320 μL) in dry acetonitrile (20 mL)were added and the mixture was heated to 70° C. for 16 hours. Further[1-(R)-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methylamine hydrochloride(170 mg) and DIPEA (100 μL) were added and the mixture was stirred at70° C. for further 4 hours. Next, the mixture was allowed to cool tor.t., taken up with AcOEt (30 mL), washed with a 1N hydrochloric acidcold solution (3×15 mL) and brine (2×10 mL). The organic layer was driedand concentrated in vacuo to a residue, which was purified by flashchromatography (CH/AcOEt 8:2) to give:

-   1. intermediate 4a (230 mg) as a white foam,-   2. intermediate 4b (231 mg) as a white foam.    Intermediate 4a

NMR (d₆-DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97(dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55(m, 1H); 2.71 (m, 2H); 2.56 (s, 31); 2.50 (m, 2H); 2.26 (s, 3H); 1.57(d, 31.

Intermediate 4b

NMR (d₆-DMSO): δ (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98(dd, 1H); 6.93 (dt, 1H); 5.29 (q, 1H); 5.24 (t, 1H); 3.56 (m, 1H); 3.48(m, 1H); 2.70 (s, 3H); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H).

Intermediate 4a

Method B:

A saturated sodium hydrogen carbonate solution (324 mL) was added to asolution of intermediate 9 (21.6 g) in AcOEt (324 mL) and the resultingmixture was vigorously stirred for 15 minutes. The aqueous layer wasback-extracted with further AcOEt (216 mL) and the combined organicextracts were dried and concentrated in vacuo to give intermediate 8 asa yellow oil, which was treated with TEA (19 mL) and AcOEt (114 mL). Thesolution obtained was added drop-wise over 40 minutes to a solution oftriphosgene (8 g) in AcOEt (64 mL) previously cooled to 0° C. under anitrogen atmosphere, maintaining the temperature between 0° C. and 8° C.

After stirring for 1 hours at 0° C. and for 3 hours at 20° C.,[1-(R)-(3,5-bis-trifluoromethylphenyl)-ethyl]-methylamine hydrochloride(29.7 g), AcOEt (190 mL) and TEA (38 mL) were added to the reactionmixture which was then heated to reflux for 16 hours.

The solution was washed with 10% sodium hydroxide solution (180 mL), 1%hydrochloric acid solution (4×150 mL), water (3×180 mL) and brine (180mL). The organic layer was dried and concentrated in vacuo to a residue,which was purified through a silica pad (CH/AcOEt 9:1) to give the titlecompound (21.5 g) as a brown thick oil.

NMR (d₆-DMSO): δ (ppm) 7.97-7.77 (bs+bs, 3H); 7.24 (dd, 1H); 6.97 (dd,1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m,2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).

Intermediate 5

2-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (5a) and2-(R)(4-Fluoro-2-methyl-phenyl) oxo-piperidine-1-carboxylic acid[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (5b)

A solution of triphosgene (147 mg) dissolved in dry DCM (5 mL) was addedto a solution of intermediate 2 (250 mg) and DIPEA (860 μL) in dry DCM(15 mL) previously cooled to 0° C. under a nitrogen atmosphere. After 2hours, a solution of[1-(S)-(3,5-bis-trifluoromethylphenyl)-ethyl]-methylamine hydrochloride(510 mg) and DIPEA (320 μL) in dry acetonitrile (20 mL) was added andthe mixture was heated to 70° C. for 16 hours. Next, further[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride(170 mg) and DIPEA (105 μL) were added. After further 4 hours at 70° C.,the mixture was allowed to cool to r.t., taken up with AcOEt (30 mL),washed with a 1N hydrochloric acid cold solution (3×15 mL) and brine(2×10 mL). The organic layer was dried and concentrated iii vacuo to aresidue, which was purified by flash chromatography (CH/AcOEt 8:2) togive:

-   1. intermediate 5a (234 mg) as a white foam,-   2. intermediate 5b (244 mg) as a white foam.    Intermediate 5a

NMR (d₆-DMSO): δ (ppm) 7.97-7.77 (bs+bs, 3H); 7.24 (dd, 1 μl); 6.97 (dd,1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m,2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).

Intermediate 5b

NMR (d₆-DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97(dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55(m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57(d, 3H).

Intermediate 6

2-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylicAcid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl Ester (6a) and2-(R)-(4-Fluoro-2-methyl-phenyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl Ester (6b)

A solution of 2-bromo-5-fluoro-toluene (3.68 g) in dry THF (10 mL) wasdropped over 30 minutes, into a mixture of magnesium (525 mg) and iodine(1 crystal) in dry THF (5 mL) previously heated to 70° C. under anitrogen atmosphere. The mixture was stirred at 70° C. for 1.5 hours,then allowed to cool to r.t.

A solution of (−)-mentyl chloroformate (3.53 mL) in dry THF (15 mL) wasadded to a solution of 4-methoxypyridine (1.52 mL) in dry THF (35 mL)previously cooled to −78° C. under a nitrogen atmosphere. After 15minutes, the solution containing the 4-fluoro-2-methylphenyl magnesiumbromide was added drop-wise, and the mixture was stirred at −78° C. for1 hour. The reaction was quenched by the addition of 1M hydrochloricacid solution (20 mL), warmed to r.t. and stirred at 23° C. for 30minutes. After extraction with AcOEt (2×150 mL), the combined organicextracts were washed with brine (50 mL), dried and concentrated in vacuoto a residue, which was purified by flash chromatography (CH/THF/toluene8:1:1) to give:

-   1. intermediate 6a (3.44 g—yellow oil)-   2. intermediate 6b (530 mg—white solid).    Intermediate 6a

T.l.c.: CH/THF/toluene 7:2:1, Rf=0.59.

IR (nujol, cm⁻¹): 1718 and 1675 (C═O).

NMR (d₆-DMSO): δ (ppm) 8.14 (d, 1H); 7.08 (dd, 1H); 7.02 (dd, 1H); 6.95(m, 1H); 5.68 (d, 1H); 5.34 (d, 1H); 4.47 (m, 1H); 3.26 (dd, 1H); 2.30(m, 4H); 1.7 (m, 4H); 1.33 (m, 2H); 0.8 (m, 11H).

Intermediate 6b

M.p.: 117-120° C.

T.l.c.: CH/THF/toluene 7:2:1, Rf=0.56.

IR (nujol, cm⁻¹): 1718 and 1669 (C═O).

NMR (d₆-DMSO): δ (ppm) 8.17 (d, 1H); 7.04-6.94 (m, 3H); 5.70 (d, 1H);5.35 (d, 1H); 4.42 (m, 1H); 3.26 (dd, 1H); 2.30 (m, 4H); 1.58-1.40 (m,3H); 1.2-0.7 (m, 81; 0.51-0.34 (bs, 6H):

Intermediate 7

2-(R)-(4-Fluoro-2-methyl-phenyl)-2,3-dihydro-1H-pyridin-4-one

Sodium methoxide (100 mg) was added to a solution of intermediate 6b(170 mg) in MeOH (15 mL) under a nitrogen atmosphere. The mixture wasrefluxed for two hours and the solvent was removed in vacuo. The residuewas partitioned between water (10 mL) and AcOEt (15 mL). The layers wereseparated, and the aqueous phase was extracted with further AcOEt (4×10mL). The combined organic extracts were washed with brine (10 mL), driedand concentrated in vacuo to give the title compound (145 mg) as a lightyellow oil.

NMR (d₆-DMSO): δ (ppm) 7.71 (bd, 1H); 7.45 (dd, 1H); 7.38 (t, 1H); 7.03(m, 2H); 4.86 (dd, 1H); 4.77 (d, 1H); 2.42 (dd, 1H); 2.3.1 (m, 4H).

MS (ES/+): m/z=206 [M+H]⁺.

Intermediate 8

2-(R)-(4-Fluoro-2-methyl-phenyl)-piperidin-4-one

Palladium over charcoal (10%-74 mg) was added to a solution ofintermediate 7 (145 mg) in MeOH (8 mL) and THF (2 mL). The mixture wasallowed to react with hydrogen in a pressure reactor (2 atm) overnight.After flushing with nitrogen, the solution was filtered and the solventremoved in vacuo. The crude product was purified by flash chromatography(AcOEt/MeOH 9:1) to give the title compound (26 mg) as a yellow oil.

The enantiomeric excess (90-95%) was detected by chiral HPLC.

T.l.c.: AcOEt/MeOH 9:1, Rf=0.2.

NMR (d₆-DMSO): δ (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27(m, 1H); 2.82 (dt, 1H); 2.72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29(s, 31); 2.25 (dt, 1H); 2.18 (m, 1H).

MS (ES/+): m/z=208 [M]⁺.

[α]_(D)=+82.1 (c=1.07, DMSO).

Intermediate 9

2-(R)-(4-Fluoro-2-methyl-phenyl)-piperidin-4-one mandelic Acid

A solution of L-(+)-mandelic acid (22.6 g) in AcOEt (308 mL) was addedto a solution of intermediate 2 (31 g) in AcOEt (308 mL). Thenisopropanol (616 mL) was added and the solution was concentrated invacuo to 274 mL. The solution was then cooled to 0° C. and further coldisopropanol (96 mL) was added. The thick precipitate was stirred undernitrogen for 5 hours at 0° C., then filtered and washed with cold Et2O(250 mL) to give the title compound as a pale yellow solid (20.3 g).

M.p.: 82-85° C.

NMR (d₆-DMSO): δ (ppm) 7.51 (dd, 1H); 7.40 (m, 21); 7.32 (m, 2H); 7.26(m, 1H); 7.0 (m, 2H); 4.95 (s, 1H); 4.04 (dd, 1H); 3.31 (m, 1H); 2.88(m, 1H); 2.49-2.2 (m, 4H); 2.29 (s, 3H). Chiral HPLC: HP 1100 HPLCsystem; column Chiralcel OD-H, 25 cm×4.6 mm; mobile phase:n-hexane/isopropanol 95:5+1% diethylamine; flow: 1.3 ml/min; detection:240/215 nm; retention time 12.07 minutes.

Intermediate 10

2-(R)-4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid(3.5-bis-trifluoromethyl-benzyl)-methylamide

Method A:

A solution of triphosgene (17 mg) in dry DCM (2 mL) was added to asolution of intermediate 8 (26 mg) and DIPEA (65 mg) in dry DCM (3 mL)previously cooled to 0° C. under a nitrogen atmosphere. After two hoursacetonitrile (10 mL) was added, the temperature was allowed to reach r.tand the DCM evaporated under a nitrogen flush. Then, a solution of3,5-bis-trifluoromethyl-benzyl)-methylamine hydrochloride (74 mg) andDIPEA (130 mg) in acetonitrile (3 mL) was added and the mixture wasstirred at 23° C. overnight. The solvent was concentrated in vacuo. Theresidue was dissolved in AcOEt (10 mL) and washed with 1N hydrochloricacid solution (3×5 mL), 5% sodium hydrogen carbonate (5 mL) and brine(10 mL). The organic layer was dried and concentrated in vacuo to aresidue, which was purified by flash chromatography (CH/AcOEt 1:1) togive the title compound (50 mg) as a white solid.

Method B:

A saturated sodium hydrogen carbonate solution (348 mL) was added to asolution of intermediate 9 (23.2 g) in AcOEt (348 mL) and the resultingmixture was vigorously stirred for 15 minutes. The aqueous layer wasback-extracted with further AcOEt (230 mL) and the combined organicextracts were dried and concentrated in vacuo to give intermediate 8(12.31 g) as a yellow oil, which was treated with TEA (20.5 mL) andAcOEt (123 mL). The solution obtained was added drop-wise over 40minutes to a solution of triphosgene (8 g) in AcOEt (61 mL) previouslycooled to 0° C. under a nitrogen atmosphere, maintaining the temperaturebetween 0° C. and 8° C.

After stirring for 2 hours at 20° C.,3,5-(bis-trifluoromethyl-benzyl)-methylamine hydrochloride (28.1 g),AcOEt (184 mL) and TEA (33 mL) were added to the reaction mixture whichwas then further stirred for 2 hours at 20° C.

The solution was washed with 10% sodium hydroxide solution (3×185 mL)and 1% hydrochloric acid solution (3×185 mL). The organic layer wasdried and concentrated in vacuo to a crude (38 g), which was purifiedthrough a silica pad (CI/AcOEt from 9:1 to 1:1) to give the titlecompound (24.7 g) as a colourless oil.

NMR (d₆-DMSO): δ (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.26 (dd, 1H); 6.98(dd, 1H); 6.90 (td, 1H); 5.23 (t, 1H); 4.61 (d, 1H); 4.41 (d, 1H); 3.60(m, 2H); 2.69 (m, 2H); 2.79 (s, 3H); 2.50 (m, 2H); 2.27 (s, 3H).

MS (ES/+): m/z=491 [MH]⁺.

Intermediate 11

3-Oxo-piperazine-1-carboxylic Acid tert-butyl Ester

Di-tert-butyl-dicarbonate (647 mg) and TEA (0.937 mL) were added to asolution of 2-oxo-piperazine (267 mg) in DCM (30 mL) under a nitrogenatmosphere. The mixture was stirred for 4 hours at r.t., thenconcentrated in vacuo to a residue which was purified by flashchromatography (AcOEt/MeOH 8:2) to give the title compound (355 mg) as awhite solid.

T.l.c.: AcOEt/MeOH 8:2, Rf=0.14.

IR (nujol, cm⁻¹): 3412 (NH), 1677 (C═O).

NMR (d₆-DMSO): δ (ppm) 6.40 (bs, 1H); 4.10 (dd, 2H); 3.64 (t, 21); 3.39(m, 2H); 1.48 (s, 9H).

MS (ES/+): m/z=201 [M+H−HCl]⁺, 223 [M−HCl+Na]⁺, 145 [M+H−tBu+H⁺.

Intermediate 12

4-Methyl-3-oxo-piperazine-1-carboxylic Acid tert-butyl Ester

Sodium hydride (60% suspension in oil, 105 mg) was added to a solutionintermediate 11 (351 mg) in anhydrous THF (30 mL) and DMF (6 mL) under anitrogen atmosphere. The mixture was stirred at r.t. for 1 hour, theniodomethane (0.218 mL) was added. The solution was warmed at 80° C. for3 hours, then was cooled to r.t. and a saturated ammonium chloridesolution was added. The organic layer was washed with iced water (20 mL)and brine (20 mL). The solution was concentrated in vacuo to give thetitle compound (195 mg) as a yellow oil.

T.l.c.: AcOEt/MeOH/TEA 80:20:1, Rf=0.51.

NMR (CDCl3): δ (ppm) 4.05 (s, 2H); 3.65 (m, 2H); 3.30 (m, 2H); 1.45 (m,9H).

Intermediate 13

{2-[1-(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methylphenyl)-piperidin-4(R)-yl-amino]-ethyl}-carbamicAcid Tert-butyl Ester (13a) and {2-[1-(3,5-Bistrifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methylphenyl)-piperidin-4-(S)-yl-amino]-ethyl}-carbamicAcid, tert-butyl Ester (13b)

N-BOC-ethylenediamine (0.109 mL) was added to a solution of intermediate10 (152 mg) in dry 1,2-dichloroethane (3 mL) and dry acetonitrile (3 mL)under a nitrogen atmosphere. The mixture was stirred at 23° C. for 16hour, then sodium triacetoxyborohydride (98 mg) was added and thesolution was stirred at 23° C. for 6 hours. The solution was washed witha 5% sodium hydrogen carbonate solution (10 mL) and brine (10 mL). Theorganic layer was dried and concentrated in vacuo to a residue which waspurified by flash chromatography (AcOEt/MeOH 8:2) to give two fractions:

-   1. intermediate 13a (65 mg)-   2. intermediate 13b (39 mg)    Intermediate 13a:

T.l.c.: AcOEt/MeOH 8:2, Rf=0.41.

NMR (d₆-DMSO): δ (ppm) 7.91 (bs, 1H); 7.62 (bs, 2H); 7.21 (dd, 1H); 6.87(dd, 1H); 6.67 (m, 1H); 6.71 (bt, 1H); 4.63 (m, 1H); 4.53 (d, 1H); 4.35(d, 1H); 3.3-2.8 (m, 5H); 2.83 (s, 3H); 2.51 (bm, 2H); 2.25 (s, 3H);1.90-1.45 (m, 4H); 1.33 (s, 9H).

MS (ES/+): m/z=635 [M+, 579 [M−tBu+H]⁺.

Intermediate 13b:

T.l.c.: AcOEt/MeOH 8:2, Rf=0.25.

NMR (d₆-DMSO): δ (ppm) 7.90 (bs 1H); 7.55 (bs 2H); 7.16 (dd, 1H); 6.85(dd, 1H); 6.73 (m, 1H); 6.64 (bt, 1H); 4.58 (d, 1H); 4.31 (d, 1H); 4.09(dd, 1H); 3.37 (m, 1H); 2.91 (m, 2H); 2.87 (s, 3H); 2.64 (m, 1H); 2.52(m, 3H); 2.30 (s, 3H); 1.89 (m, 2H); 1.82 (m, 2H), 1.31 (s, 9H). MS(ES/+): m/z=635 [MH]⁺, 579 [M−tBu+H]⁺.

Intermediate 14

{2-[1-{[1-(R)-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-methyl-carbamoyl}-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-(R)-yl-amino]-ethyl}-carbamicAcid tert-butyl Ester (14a) and{2-[1-{1-(R)-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-methyl-carbamoyl}-2-(R)-(4-fluoro-2-methyl-phenyl)piperidin-4-(S)-yl-amino]-ethyl}-carbamicAcid tert-butyl Ester (14b)

N-BOC-ethylenediamine (0.435 ml) was added to a solution of intermediate4a (462 mg) in dry 1,2-dichloroethane (9 mL) and dry acetonitrile (9 mL)under a nitrogen atmosphere. The mixture was stirred at 23° C. for 30minutes, then sodium triacetoxyborohydride (298 mg) was added. Thesolution was stirred at 23° C. for 16 hours, then washed with a 5%sodium hydrogen carbonate solution (10 mL) and brine (10 mL). Theorganic layer was dried and concentrated in vacuo to a residue which waspurified by flash chromatography (AcOEt/MeOH 9:1) to give two fractions.

-   1. intermediate 14a (252 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.42).-   2. intermediate 14b (116 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.34).    Intermediate 14a:

NMR (d₆-DMSO): δ (ppm) 7.98 (bs, 1H); 7.71 (bs, 2H); 7.23 (dd, 1H); 6.92(dd, 1H); 6.80 (dt, 1H); 6.74 (bt, 1H); 5.22 (q, 1H); 4.73 (dd, 1H);3.27 (m, 1H); 3.09 (m, 1H); 3.01 (m, 2H); 2.87 (m, 2H); 2.66 (s, 3H);2.52 (m, 2H); 2.28 (s, 3H); 1.87 (m, 1H); 1.80 (bs, 11H); 1.65 (m, 2H);1.49 (m, 4H); 1.37 (s, 9H).

MS (ES/+): m/z=649 [M+H]⁺; 593 [M−tBu+H]⁺, 549 [M+H-BOC+H].

Intermediate 14b:

NMR (d₆-DMSO): δ (ppm) 7.99 (s, 1H); 7.68 (s, 2H); 7.14 (dd, 1H); 6.90(dd, 1H); 6.76 (dt, 1H); 6.70 (bs, 1H); 5.31 (m, 1H); 4.13 (dd, 1H); 3.3(m, 2H); 2.97 (m, 3H); 2.72 (s, 3H); 2.59 (bs, 2H); 2.34 (s, 3H);1.8-1.4 (bm, 5H); 1.46 (d, 3H); 1.36 (s, 91.

MS (ES/+): m/z=649 [M+H]⁺, 593 [M−tBu+H]⁺.

Intermediate 15

(2-Cyclopropylamino-ethyl)-carbamic Acid tert-butyl Ester

Cyclopropylamine (866 μl) was added to a solution oftert-butyl-N-(2-oxo-ethyl)carbammate (1 g) in MeOH (50 mL) under anitrogen atmosphere. The resulting solution was stirred at 23° C. for 1hour, then potassium borohydride (372 mg) was added and the mixture wasstirred at 23° C. for a further 1 hour. The mixture was concentrated tohalf volume, diluted with a saturated sodium hydrogen carbonate solution(20 mL) and extracted with AcOEt (2×30 mL). The combined organicextracts were dried, concentrated in vacuo to a residue, which waspurified by flash chromatography (AcOEt/MeOH 9:1) to give the titlecompound (1.22 g) as a yellow oil.

NMR (CDCl3): δ (ppm) 8.25 (bm, 1H); 3.2 (dd, 2H); 2.8 (dd, 2H); 2.1 (m,1H); 1.42 (s, 9H); 0.42 (dd, 2H); 0.29 (m, 2H).

MS (ES/+): m/z=201 [M+H⁺, 145 [M−tBu]⁺.

Intermediate 16

{2-[(2-Bromoacetyl)-cyclopropyl-amino]-ethyl}carbamic Acid tert-butylEster

TEA (719 μL) and bromoacetylbromide (0.27 μL) were added to a solutionof intermediate 15 (511 mg) in anhydrous DCM (25 mL) previously cooledto 0° C. under a Nitrogen atmosphere. The solution was stirred at 0° C.for 30 minutes, then it was quenched with brine (15 mL). The layers wereseparated and the organic phase was dried and concentrated in vacuo. Theresidue was purified by flash chromatography (CH/AcOEt 65:35) to givethe title compound (394 mg) as a yellow solid.

T.l.c.: CH(AcOEt 1:1, Rf=0.43 (detection only with ninhydrin).

NMR (CDCl3): δ (ppm) 4.85 (bm, 1H); 4.1 (s, 2H); 3.5 (m, 2H); 3.3 (m,2H); 2.88 (m, 1H); 1.42 (s, 9H); 0.95 (m, 2H); 0.85 (m, 2H).

Intermediate 17

4-Cyclopropyl-3-oxo-piperazine-1-carboxylic acid tert-butyl Ester

Sodium hydride (60% dispersion in mineral oil —147 mg) was added to asolution of intermediate 16 (394 mg) in anhydrous THF (12 mL) and DMF(12 mL) previously cooled to 0° C. under a Nitrogen atmosphere. Themixture was stirred at 0° C. for 1.5 hours, then water (20 mL) was addedand the mixture was extracted with AcOEt (3×30 mL). The combined organicextracts were washed with cold water (20 mL) and brine (20 mL), driedand concentrated in vacuo. The residue was purified by flashchromatography (CH/AcOEt 1:1) to give the title compound (210 mg) as ayellow oil.

T.l.c.: CH/AcOEt 1:1, Rf==0.23 (detection only with ninhydrin).

NMR (CDCl3): δ (ppm) 5.5 (m, 2H); 4.0 (s, 2H); 3.23 (m, 2H); 2.7 (m,1H); 1.42 (s, 9H); 0.8 (m, 2H); 0.65 (m, 2H).

Intermediate 18

4-(R)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methylphenyl)-piperidin-4-yl]-piperazine-1-carboxylicAcid tert-butyl Ester (18a) and4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)methyl-carbamoyl]-2-(R)-(4-fluoro-2-methylphenyl)-piperidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (18b)

A solution of intermediate 10 (400 mg) andN-tert-butoxycarbonyl-piperazine (151.8 mg) in dry 1,2-dichloroethane(10 mL) was stirred at r.t. for 30 minutes under a nitrogen atmosphere.Then, sodium triacetoxyborohydride (0.310 mg) was added and the mixturewas stirred at 23° C. for 24 hours. The solution was diluted with AcOEtand washed with water. The organic layer was dried and concentrated invacuo to a residue, which was purified by flash chromatography(AcOEt/MeOH from 9:1) to give:

-   intermediate 18a (181 mg),-   intermediate 18b (155 mg).    Intermediate 18a:

T.l.c.: AcOEt/MeOH 8:2, Rf=0.35.

IR (nujol, cm⁻¹): 1703 and 1651 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.91 (s, 1H); 7.65 (s, 2H); 7.26 (dd, 1H); 6.89(dd, 1H); 6.79 (bt, 1H); 4.78 (dd, 1H); 4.52 (d, 1H); 4.37 (d, 1H); 3.25(m, 6H); 3.09 (m, 1H); 2.78 (s, 3H); 2.37 (bs, 4H); 2.22 (s, 3H); 1.86(m, 1H); 1.78 (m, 1H); 1.68 (m, 2H); 1.35 (s, 9H).

MS (ES/+): m/z=661 [MH]⁺.

Intermediate 18b

T.l.c.: AcOEt/MeOH 8:2, Rf=0.14.

IR (nujol, cm⁻¹): 1702 and 1654 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.90 (s, 1H); 7.56 (s, 2H); 7.18 (dd, 1H); 6.85(dd, 1H); 6.73 (dt, 1H); 4.59 (d, 1H); 4.32 (d, 1H); 4.1 (dd, 1H); 3.41(bm, 1H); 3.21 (bs, 4H); 2.87 (s, 3H); 2.64 (t, 1H); 2.5 (m, 1H); 2.39(bs, 4H); 2.3 (s, 3H); 1.82 (bs, 1H); 1.73 (m, 1H); 1.56 (dq, 1H); 1.33(s, 9H); 1.33 (q, 1H).

MS (ES/+): m/z=661 [MH]⁺.

EXAMPLES 1a and 1b2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicAcid (3,5-bis-trifluoromethyl-benzyl)-methylamide (Example 1a)2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicAcid (3,5-bis-trifluoromethyl-benzyl)-methylamide (Example 1b)

Piperazin-2-one (60 mg) was added to a solution of intermediate 10 (150mg) in dry 1,2-dichloroethane (3 mL) and dry acetonitrile (3 mL) under aNitrogen atmosphere. The mixture was stirred at 23° C. for 16 hour, thensodium triacetoxyborohydride (97 mg) was added. The solution was stirredat 23° C. for 6 hours, then washed with a 5% sodium hydrogen carbonatesolution (10 mL) and brine (10 mL). The organic layer was dried andconcentrated in vacuo to a residue which was purified by flashchromatography (AcOEt/MeOH 9:1) to give two fractions:

-   1. example 1a (23 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.24)-   2. example 1b (56 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.11).

Example 1a

IR(nujol, cm⁻¹): 3350 (NH⁺), 1734 and 1635 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.94 (s, 1H); 7.78 (s, 1H); 7.66 (s, 2H); 7.30(m, 1H); 6.93 (dd, 1H); 6.83 (m, 1H); 4.75 (dd, 1H); 4.58 (d, 1H); 4.40(d, 1H); 3.3 (m, 2H); 3.10-3.00 (m, 4H); 3.83 (s, 3H); 2.70-2.50 (m,3H); 2.27 (s, 3H); 2.00+1.60 (m, 4H).

MS (ES/+): m/z=575 [M+H]⁺.

Example 1b

IR (nujol, cm⁻¹): 3213 (NH⁺), 1737 and 1657 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.94 (s, 1H); 7.66 (s, 1H); 7.59 (s, 2H), 7.25(dd, 1H); 6.89 (dd, 1H); 6.77 (m, 1H); 4.62 (d, 1H); 4.37 (d, 1H); 4.14(dd, 1H); 3.46-3.04 (m, 4H); 2.90 (s, 3H); 1.88-1.36 (m, 4H).

MS (ES/+): m/z=1575 [M+H]⁺.

EXAMPLE 22-(R)-(4-Fluoro-2-methyl-phenyl-4-(R)-(3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicAcid (3,5-bis-trifluoromethyl-benzyl)methylamide hydrochloride

Hydrochloric acid (1M in Et₂O —0.3 mL) was added to a solution ofexample 1a (23 mg) in dry Et2O (3 mL) previously cooled to 0° C. under anitrogen atmosphere. The resulting solution was stirred at 0° C. for 30minutes, then it was concentrated in vacuo to give the title compound(18 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 10.87 (bs, 1H); 8.46 (bs, 1H); 7.81 (s, 1H); 7.79(s, 2H); 7.36 (m, 1H); 6.97 (m, 2H); 4.49 (q, 2H); 3.87-3.13 (bm, 9H);2.76 (s, 3H); 2.25 (s, 3H); 2-0.5 (m, 4H).

MS (ES/+): m/z=575 [M+H−HCl]⁺, 597 [M−HCl+Na]⁺.

EXAMPLE 32-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicAcid (3,5-bis-trifluoromethyl-benzyl)-methylamide Hydrochloride

Hydrochloric acid (1M in Et₂O —0.5 mL) was added to a solution ofexample 1b (56 mg) in dry Et₂O (5 mL) previously cooled to 0° C. under anitrogen atmosphere. The resulting solution was stirred at 0° C. for 30minutes, then it was concentrated in vacuo to give the title compound(46 mg) as a white solid.

IR (nujol, cm⁻¹): 3421 (NH⁺), 1676 (C═O).

NMR (d₆-DMSO): δ (ppm) 10.84 (bs, 1H); 8.41 (s, 1H); 7.95 (s, 1H); 7.59(s, 1H); 7.28 (m, 1 h) 6.92 (dd, 1H); 6.82 (m, 1H); 4.62 (d, 1H); 4.37(d, 1H); 4.19 (dd, 1H); 3.9-3.2 (m, 7H); 2.82 (s, 3H); 2.75 (m, 1H);2.37 (s; 3H); 2.25+2.7, (m, 4H).

MS (ES/+): m/z=575 [M+H−HCl]⁺, 597 [M−HCl+Na]⁺.

EXAMPLES 4a AND 4b2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(4-methyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicAcid (3,5-bis-trifluoromethyl-benzyl)-methylamide (4a)2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-methyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicAcid (3,5-bis-trifluoromethyl-benzyl)-methylamide (4b)

TFA (0.8 mL) was added to a solution of intermediate 12 (190 mg) in DCM(8 mL) previously cooled to 0° C. under a nitrogen atmosphere. Themixture was stirred at r.t. for 4 hours, then it was concentrated invacuo to give 1-methyl-piperazin-2-one trifluoroacetate (102 mg) whichwas used as a crude in the following reactions.

1-Methyl-piperazin-2-one trifluoroacetate (102 mg) and TEA (0.185 mL)were added to a solution of intermediate 10 (217 mg) in drydichloroethane (6 mL) and dry acetonitrile (6 mL) under a nitrogenatmosphere. The mixture was stirred at 23° C. for 16 hours, then sodiumtriacetoxyborohydride (281 mg) was added and the solution was stirredfor 6 hours. The mixture was washed with a 5% sodium hydrogen carbonatesolution (10 mL) and brine (10 mL). The organic layer was dried andconcentrated in vacuo, to a residue which was purified by flashchromatography (AcOEt/MeOH 9:1) to give two fractions:

-   1. example 4a (56 mg—T.l.c.: AcOEt/MeOH 8:2, Rf==0.33),-   2. example 4b (42 mg—T.l.c.: AcOEt/MeOH 8:2, Rf==0.13).

Example 4a

IR (nujol, cm⁻¹): 1649 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.95 (bs, 1H); 7.66 (bs, 2H); 7.22; (dd, 1H);6.93 (dd, 1H); 6.83 (dt, 1H); 4.72 (dd, 1H); 4.58 (d, 1H); 4.39 (d, 1H);3.3-3.1 (m, 2H); 3.9-2.6 (m, 1H); 2.53 (m, 4H); 3.09 (m, 2H); 2.84 (s,3H); 2.83 (s, 3H); 2.28 (s, 3H); 1.95-1.65 (m, 4H).

MS (ES/+): m/z=589 [M+H]⁺.

Example 4b

IR (nujol, cm⁻¹): 1650 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.94 (bs, 1H); 7.59 (bs, 2H); 7.24 (dd, 1H); 6.90(dd, 1H); 6.77 (dt, 1H); 4.62 (d, 1H); 4.37 (d, 1H); 4.13 (dd, 1H); 3.46(m, 1H); 3.20 (m, 2H); 3.10 (m, 21); 2.91 (s, 3H); 2.78 (s, 3H);2.80-2.50 (m, 4H); 2.35 (s, 3H); 1.89 (m, 1H); 1.83 (m, 1H); 1.61 (m,1H); 1.34 (q, 1H).

MS (ES/+): m/z=589 [M+H]⁺, 611 [M+Na]⁺.

EXAMPLE 52-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(4-methyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicAcid (3,5-bis-trifluoromethyl-benzyl)methylamide hydrochloride

A solution of example 4a (56 mg) in dry Et₂O (5 mL) was treated withhydrochloric acid (1M in Et₂O —0.5 mL) and the resulting solution wasstirred at 23° C. for 30 minutes. The solution was concentrated in vacuoto give the title compound as a white solid (26 mg).

IR (nujol, cm⁻¹): 1653 (C═O).

NMR (d₆-DMSO): δ (ppm) 11.10 (bs, 1H); 7.95 (s, 1H); 7.59 (s, 2H); 7.27(bt, 1H); 6.93 (d, 1H); 6.82 (bt, 1H); 4.62 (d, 1H); 4.37, (d, 1H); 4.37(d, 1H); 4.18 (d, 11; 3.95-3.25 (m, 7H); 2.93 (s, 3H); 2.86 (s, 3H);2.72 (t, 1H); 2.37 (s, 3H); 2.20-2.08 (m, 2H); 1.90 (bm 1H); 1.8-1.6(bm, 1H).

MS (ES/+): m/z=589 [MH−HCl], 611 [M−HCl+Na]⁺.

EXAMPLE 62-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-4-methyl-3-oxo-piperazin-1-yl-)-piperidinecarboxylic Acid (3.5-bis-trifluoromethyl-benzyl)-methylamideHydrochloride

A solution of example 4b (42 mg) in dry Et₂O (4 mL) was treated withhydrochloric acid (1M in Et₂O—0.4 mL) and the resulting solution wasstirred at 23° C. for 30 minutes. The solution was concentrated in vacuoto give the title compound (28 mg) as a white solid.

IR (nujol, cm⁻¹): 3395 (NH⁺), 2800-2500 (NH), 1665 (C═O), 1623 (C═C).

NMR (d₆-DMSO): δ (ppm) 10.93 (bs, 1H); 7.98 (bs, 1H); 7.78 (bs, 2H);7.36 (bm, 1H); 7.01 (bm, 1H); 6.92 (bm, 1H); 5.19 (bm, 1H); 4.59 (d,1H); 4.41 (d, 1H); 4.1-3 (bm, 9H); 2.89 (s, 3H); 2.76 (s, 3H); 2.5-2.0(bm, 6H); 1.80 (bm, 1H).

MS (ES/+): m/z=589 [MH−HCl]⁺.

EXAMPLE 72-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-methyl-3-oxo-piperazin-1-yl)-piperidine-1-carboxylicAcid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamideHydrochloride

TFA (1 mL) was added to a solution of intermediate 12 (210 mg) in DCM (9mL) previously cooled to 0° C. under a nitrogen atmosphere. The mixturewas stirred at r.t. for 4 hours, then was concentrated in vacuo to give1-methyl-piperazin-2-one trifluoroacetate (210 mg) which was dissolvedin DCM (10 mL) and the mixture treated with solid potassium carbonate.The inorganic material was filtered off and the solution wasconcentrated in vacuo to give 1-methyl-piperazin-2-one (111 mg). Theresidue was added to a solution intermediate 4b (245 mg) in dry1,2-dichloroethane (4 mL) and dry acetonitrile (4 mL) under a nitrogenatmosphere. The mixture was stirred at 23° C. for 16 hours, then sodiumtriacetoxyborohydride (354 mg) was added. The solution was stirred at23° C. for 3 days, then washed with a 5% sodium hydrogen carbonatesolution (10 mL) and brine (10 mL). The organic layer was dried andconcentrated in vacuo to a residue which was purified by flashchromatography (AcOEt/MeOH 98:2) to give three fractions:

-   1. diastereoisomer 1 (C-2 and C-4 anti configuration—9 mg—T.l.c.:    AcOEt/MeOH 9:1, Rf==0.27).-   2. mixture of the two diastereoisomers (104 mg).

3. diastereoisomer 2 (C-2 and C-4 syn configuration—24 mg—T.l.c.:AcOEt/MeOH 9:1, Rf==0.22).

A solution of diastereoisomer 2 (24 mg) in dry Et₂O (1 mL) was treatedwith hydrochloric acid (1M in Et₂O —0.2 mL). The resulting solution wasstirred at 0° C. for 30 minutes, then it was concentrated in vacuo togive the title compound (13 mg) as a white solid.

NMR (d₆-DMSO, 70° C.): δ (ppm) 11 (bs, 1H); 7.92 (s, 1H); 7.67 (s, 2H);7.23 (dd, 1H); 6.90 (dd, 1H); 6.79 (m, 1H); 5.32 (q, 1H); 4.21 (dd, 1H);3.5-2.8 (m, 9H); 2.10 (m, 2H); 1.8 (m, 1H); 1.7 (m, 1H); 2.86 (s, 3H);2.74 (s, 3H); 2.37 (s, 3H); 1.47 (d, 3H).

MS (ES/+): m/z=603 [M+H−HCl]⁺.

EXAMPLE 82-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(2-oxo-piperazin-1-yl)-piperidine-1-carboxylicAcid (3,5-bis-trifluoromethyl-benzyl)methylamide Hydrochloride

Bromoacetylbromide (5 μL) and TEA (13 μL) were added to a solution ofintermediate 13a (29 mg) in dry DCM (0.5 mL) previously cooled to 0° C.under a nitrogen atmosphere. The solution was stirred at 0° C. for 30minutes, then it was washed with brine. The organic layer was dried andconcentrated in vacuo to give{2-[1-(3,5-bis-trifluoromethyl-benzyl)-methylcarbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-(R)-yl]-2-bromo-acetyl)-amino-ethyl}-carbamicacid tert-butyl ester (28 mg), which was used without furtherpurification in the next reactions.

TFA (0.1 mL) was added to a solution of this material (28 mg) in dry DCM(0.9 mL), previously cooled to 0° C. under a nitrogen atmosphere. Themixture was stirred at 23° C. for 1 hour. The organic layer was washedwith a saturated solution of sodium hydrogen carbonate (1 mL) and brine(1 mL), then dried. After concentration in vacuo, the residue waspurified by flash chromatography (AcOEt/MeOH 9:1) to give of2-(R)-(4-fluoro-2-methyl-phenyl)-4-(R)-(2-oxo-piperazin-1-yl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide (11 mg).

This material (11 mg) was dissolved in dry Et₂O (1 mL) and treated withhydrochloric acid (1M in Et₂O —0.1 mL). The resulting solution wasstirred at 23° C. for 30 minutes, then concentrated in vacuo to give thetitle compound (6 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 9.19 (bs, 2H); 8.00 (s, 1H); 7.88 (s, 2H); 5.75(m, 1H); 7.24-6.98 (m, 1H); 5.31 (bs, 1H); 4.8 (bs, 1H); 4.56 (d, 1H);4.46 (d, 1H); 3.6 (m, 1H); 3.4 (m, 6H); 3.00 (m, 1H); 2.73 (s, 3H); 2.16(s, 3H); 2.1 (m, 1H); 1.9 (m, 1H); 1.6 (m, 2H). MS (ES/+): m/z=575[M+H−HCl]⁺.

EXAMPLE 92-(R)-(4-Fluoro-2-meth-phenyl)-4-(S)-(2-oxo-piperazin-1-yl-piperidine-1-carboxylicAcid (3,5-bis-trifluoromethyl-benzyl)-methylamide

Bromoacetylbromide (7 μL) and TEA (18 μL) were added to a solution ofintermediate 13b (41 mg) in dry DCM (0.6 mL) previously cooled to 0° C.under a nitrogen atmosphere. The solution was stirred at 0° C. for 30minutes. The organic layer was washed with brine, dried and concentratedin vacuo to give {2-[1-(3,5-bistrifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-(S)-yl]-2-bromo-acetyl)amino-ethyl}-carbamicacid tert-butyl ester (19 mg), which was used without furtherpurification for the next reaction.

TFA (0.05 mL) was added to a solution of this material (18 mg) in dryDCM (0.45 mL), previously cooled to 0° C. under a nitrogen atmosphere.The mixture was stirred at 23° C. for 1 hour. The organic layer waswashed with a saturated solution of sodium hydrogen carbonate (1 mL) andbrine (1 mL), then dried. The residue was purified by flashchromatography (AcOEt/MeOH 8:2) to give the title compound (5.5 mg) as awhite foam.

MS (ES/+): m/z=575 [M+H]⁺.

EXAMPLE 102-(4-Fluoro-2-methyl-phenyl)-4-(S)-(2-oxo-piperazin-1-yl)-piperidine-carboxylicAcid (3,5-bis-trifluoromethyl-benzyl)-methylamide Hydrochloride

Hydrochloric acid (1M in Et₂O —0.05 mL) was added to a solution ofexample 9 (5.5 mg) in dry Et₂O (0.5 mL) previously cooled to 0° C. undera nitrogen atmosphere. The resulting solution was stirred at 0° C. for30 minutes, then concentrated in vacuo to give the title compound (3 mg)as a white solid.

NMR (d₆-DMSO): δ (ppm) 9.19 (bs, 2H); 8.0 (s, 1H); 7.88 (s, 2H); 5.75(m, 1H); 7.24-6.98 (m, 1H); 5.31 (bs, 1H); 4.8 (bs, 1H); 4.56 (d, 1H);4.46 (d, 1H); 3.6 (m, 1H); 3.4 (m, 6H); 3.0 (m, 1H); 2.73 (s, 3H); 2.16(s, 3H); 2.1 (m, 1H); 1.9 (m, 1H); 1.6 (m, 21).

MS (ES/+): m/z=575 [M+H−HCl]⁺.

EXAMPLE 112-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(2-oxo-4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide

Formaldehyde (37% in water, 0.093 mL) was added to a solution example 9(270 mg) in 1,2-dichloroethane (4 mL). The mixture was stirred for 15minutes at room temperature, then sodium triacetoxyborohydride (149 mg)was added. The solution was stirred for 3 hours at 23° C., then it waswashed with 5% sodium hydrogen carbonate solution (10 mL) and brine. Theorganic layer was dried and concentrated in vacuo to a residue which waspurified by flash chromatography (AcOEt/MeOH 8:2) to give2-(R)-(4-fluoro-2-methyl-phenyl)-4-(S)-(2-oxo-4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide (120 mg).

This material (120 mg) was dissolved in dry Et₂O (2 mL) and treated withhydrochloric acid (1M in Et₂O —0.4 mL). The resulting solution wasstirred at 0° C. for 30 minutes, then it was concentrated in vacuo togive the title compound (90 mg) as a white solid.

IR (nujol, cm⁻¹): 1653 (C═O).

NMR (d₆-DMSO):δ (ppm) 10.6 (bs, 1H); 7.95 (s, 1H); 7.60 (2.25, 211);7.28 (dd, 1H); 6.92 (dd, 1H); 6.80 (t, 1H); 4.64 (d, 1H); 4.44 (t, 1H);4.38 (d, 1H); 4.23 (dd, 1H); 4-3.2 (bm, 5H); 2.92 (s, 31); 2.8 (m, 2H);2.9-2.5 (sb, 3H); 2.34 (s, 3H); 1.98 (m, 2H); 1.75-1.55 (m, 2H).

MS (ES/+): m/z=589 [M+H−HCl]⁺.

EXAMPLE 12 2-(R)-(4-Fluoro-2-methyl-phenyl)(S)-(4-methyl-2-oxo-piperazin-1-yl)-piperidine-1-carboxylic Acid[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide

Bromoacetylbromide (0.027 mL) and TEA (0.073 mL) were added to asolution of intermediate 14b (162 mg) in dry dichloromethane (2 mL)previously cooled to 0° C. under a nitrogen atmosphere. The solution wasstirred at 0° C. for 30 minutes. The organic layer was washed withbrine, dried and the solution concentrated in vacuo to give{2-[1-{[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-carbamoyl}-2(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-(S)-yl]-2-bromo-acetyl)-amino]-ethyl}-carbamicacid tert-butyl ester (200 mg), which was used without furtherpurification in the next reaction.

TFA (0.2 mL) was added to a solution of this compound (200 mg) in drydichloromethane (1.8 mL) previously cooled to 0° C. under a nitrogenatmosphere. The mixture was stirred at 23° C. for 3 hours, then washedwith a saturated solution of sodium hydrogen carbonate (1 mL) and brine(1 mL), then dried and concentrated in vacuo. The residue was purifiedby flash chromatography (AcOEt/MeOH 8:2) to give the title compound (49mg).

NMR (d₆-DMSO): δ (ppm) 7.75 (bs, 1H); 7.55 (bs, 2H); 7.15 (dd, 1H); 6.8(m, 2H); 5.55 (q, 1H); 4.7 (bm, 1H); 4.35 (dd, 1H); 3.6-2.9 (m, 6H); 2.7(s, 3H); 2.4 (s, 3H); 2.5-2.0 (bm, 2H); 2.0-1.5 (m, 4H); 1.4 (d, 3H).

EXAMPLE 132-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-methyl-2-oxo-piperazin-1-yl)-piperidine-1-carboxilicAcid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamideHydrochloride

Formaldehyde (37% in water, 0.012 mL) was added to a solution of example12 (49 mg) in acetonitrile (8 mL). The mixture was stirred for 30minutes at room temperature, then sodium triacetoxyborohydride (26 mg)was added. The solution was stirred for 4 hours at 23° C. andconcentrated in vacuo. The residue was dissolved in DCM and the organiclayer washed with 5% sodium hydrogen carbonate solution (10 mL) andbrine, then dried and concentrated in vacuo. The residue was purified byflash chromatography (AcOEt/MeOH 9:1) to give 2-(R)(4-fluoro-2-methyl-phenyl)-4-(S)-(4-methyl-2-oxo-piperazin-1-yl)-piperidine-1-carboxylicacid [1 (R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (22 mg).

This material (22 mg) was dissolved in dry Et₂O (2.5 mL) and treatedwith hydrochloric acid (1M in Et₂O —0.2 mL). The solution was stirred at0° C. for 30 minutes, then it was concentrated in vacuo to give thetitle compound (18 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 10.82 (bs, 1H); 7.96 (s, 1H); 7.55 (s, 2H); 7.18(dd, 1H); 6.86 (dd, 1H); 6.75 (dt, 1H); 5.3 (q, 1H); 4.41 (bt, 1H); 4.18(dd, 1H); 3.9-3.4 (many bs, 6H); 3.37 (m, 1H); 2.8 (m, 1H); 2.74 (bs,3H); 2.69 (bs, 3H); 2.3 (bs, 3H); 1.93 (m, 1H); 1.75 (q, 1H); 1.63 (bd,1H); 1.54 (bd, 1H); 1.43 (d, 3H).

MS (ES/+): m/z=603 [M+H−HCl]⁺.

EXAMPLES 14a AND 14b2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(4-cyclopropyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicAcid 1-(3,5-bis-trifluoromethyl-benzyl)-methylamide Hydrochloride (14a)2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-cyclopropyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicAcid 1-(3,5-bis-trifluoromethyl-benzyl)-methylamide Hydrochloride (14b)

TFA (2.5 mL) was added to a solution of intermediate 17 (254 mg) inanhydrous DCM (7.5 mL) previously cooled to 0° C. under a nitrogenatmosphere. The solution was allowed to warm to r.t. and stirred at 23°C. for 1 hour. The solution was concentrated in vacuo to give the crude1-cyclopropyl-piperazine trifluoroacetate (269 mg), which was usedwithout any further purification.

TEA (443 μL) and a solution of 1-cyclopropyl-piperazine trifluoroacetate(269 mg) in 1,2-dichloroethane (5 mL) were added to a solution ofintermediate 10 (486 mg) in dry 1-2-dichloroethane (20 mL) under anitrogen atmosphere. The resulting mixture was stirred at r.t. for 30minutes, then sodium triacetoxyborohydride (334 mg) was added and theresulting mixture was stirred at 23° C. for 16 hours. A 5% sodiumhydrogen carbonate solution (20 mL) was added, the layers were separatedand the aqueous layer was extracted with further DCM (20 mL). Thecombined extracts were dried and concentrated in vacuo. The residue waspurified by flash chromatography (from AcOEt to AcOEt/MeOH 95:5) to givetwo fractions:

-   -   diastereoisomer 1 (106 mg—T.l.c. AcOEt/MeOH 95:5, Rf=0.18)    -   diastereoisomer 2 (220 mg—T.l.c. AcOEt/MeOH 95:5, Rf==0.09).

Example 14a

A solution of diastereoisomer 1 (99 mg) in dry Et₂O (2 mL) was treatedwith hydrochloric acid (1M in Et₂O —0.177 mL) at 0° C. and the resultingmixture was stirred at 0° C. for 30 minutes. The solution wasconcentrated in vacuo and the residue was triturated with pentane togive the title compound as a yellow solid (70 mg).

NMR (d₆-DMSO): δ (ppm) 10.66 (bs, 1H); 7.98 (bs, 1H); 7.78 (bs, 2H);7.35 (bm, 1H); 6.99 (bm, 1H); 6.92 (bm, 1H); 5.17 (bm, 1H); 4.58 (d,1H); 4.41 (d, 1H); 4.0-2.73 (many bm, 10H); 2.76 (s, 3H); 2.25 (s, 3H);2.16 (bm, 2H); 1.77 (bm, 2H); 0.74 (bs, 2H); 0.65 (bs, 2H).

MS (ES/+): m/z=614 [M+H−HCl]⁺.

Example 14b

A solution of diastereoisomer 2 (149 mg) in dry Et₂O (3 mL) was treatedwith hydrochloric acid (1M in Et₂O —0.27 mL) at 0° C. and the resultingmixture was stirred at 0° C. for 30 minutes. The solution wasconcentrated in vacuo and the residue was triturated with pentane togive the title compound as a white solid (115 mg).

NMR (d₆-DMSO): δ (ppm) 11.23 (bs, 1H); 7.95 (s, 1H); 7.58 (s, 2H); 7.28(m, 1H); 6.94 (dd, 1H); 6.82 (dt, 1H); 4.62 (d, 1H); 4.37 (d, 1H); 4.18(bd, 1H); 4.0-3.0 (bm, 8H); 2.92 (s, 3H); 2.7 (m, 2H); 2.37 (s, 3H);2.2-1.6 (bm, 4H); 0.72 (bd, 2H); 0.63 (bd, 2H).

MS (ES/+): m/z=614 [M+H−HCl]⁺.

EXAMPLE 152-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)(1-methanesulfonyl-piperazin-1-yl)-piperidine-1-carboxylicacid 1-(3,5-bis-trifluoromethyl-benzyl)methylamide

TFA (1 mL) was added to a solution of intermediate 18b (155 mg) inanhydrous DCM (5 mL). The solution was stirred at r.t. for 3 hours, thenit was concentrated in vacuo. The residue was diluted in a saturatedpotassium carbonate solution (10 mL) and extracted with DCM (2×20 mL)and AcOEt (20 mL). The combined organic extracts were dried andconcentrated in vacuo to give4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine(104 mg) as an oil.

T.l.c.: AcOEt/MeOH 8:2, Rf=0.12. IR (nujol, cm⁻¹): 1653 (C═O).

NMR (d₆-DMSO): δ (ppm) 7.94 (s, 1H); 7.59 (s, 2H); 7.22 (dd, 1H); 6.89(dd, 1H); 6.77 (dt, 1H); 4.62 (d, 1H); 4.36 (d, 1H); 4.13 (dd, 1H); 3.44(dt, 1H); 3.3 (m, 1H); 2.9 (s, 3H); 2.67 (m, 1H); 2.65 (m, 4H); 2.4 (bm,4H); 2.34 (s, 3H); 1.86 (bd, 1H); 1.77 (bd, 1H); 1.6 (dq, 1H); 1.34 (q,1H). MS (ES/+): m/z=561 [MH]⁺.

80 mg of such an oil was dissolved in in anhydrous DCM (3 mL) thesolution was cooled at 0° C. under a nitrogen atmosphere and thenmethanesulfonyl chloride (11.8 μL) Methanesulfonyl chloride (11.8 μL)and TEA (40 μL) were added to a solution The solution was stirred at 0°C. for 4 hours, then it was washed with saturated sodium hydrogencarbonate solution (5 mL). The layers were separated and the organicphase was extracted with further DCM (3×5 mL). The combined organicextracts were dried and concentrated in vacuo to a residue, which waspurified by flash chromatography (AcOEt/MeOH 9:1) to give the titlecompound (60 mg) as a colourless oil.

T.l.c.: AcOEt/MeOH 9:1, Rf=0.27.

NMR (d₆-DMSO): δ (ppm) 7.93 (s, 1H); 7.59 (s, 2H); 7.23 (dd, 1H); 6.89(dd, 1H); 6.77 (dt, 1H); 4.62 (d, 1H); 4.36 (d, 1H); 4.14 (dd, 1H); 3.46(m, 1H); 3.3 (m, 1H); 3.04 (m, 4H); 2.9 (s, 3H); 2.83 (s, 3H); 2.67 (t,1H); 2.5 (m, 41); 2.34 (s, 3M); 1.9-1.75 (m, 2H); 1.65 (m, 1H); 1.38 (m,1H).

MS (ES/+): m/z=639 [MH]⁺.

EXAMPLE 162-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)(1-methanesulfonyl-piperazin-1-yl)-piperidine-1-carboxylicAcid (3,5-bis-trifluoromethyl-benzyl)-methylamide Hydrochloride

A solution of example 17 (58 mg) in dry Et₂O (2 mL) was treated withhydrochloric acid (1M in Et₂O—0.1 mL) at 0° C. and the resulting mixturewas stirred at 0° C. for 30 minutes. The solution was concentrated invacuo and the residue was triturated with pentane to give the titlecompound as a white solid (53 mg).

NMR (d₆-DMSO): 6 (ppm) 10.09 (bs, 1H); 7.96 (bs, 1H); 7.61 (bs, 2H);7.27 (m, 1H); 6.96 (m, 1H); 6.84 (m, 1H); 4.64 (d, 1H); 4.37 (d, 1H);4.22 (d, 1H); 3.8-3.5 (m, 2H); 3.5-2.9 (m, 8H); 3.02 (s, 3H); 2.94 (s,3H); 2.76 (m, 1H); 2.38 (m, 3H); 2.17 (m, 2H); 1.88 (m, 1H); 1.69 (m,1H).

MS (ES/+): m/z=639 [MH−HCl]⁺.

EXAMPLE 172-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)(1-methanesulfonyl-piperazin-1-yl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide

A solution of intermediate 4a (160 mg), N-tert-butoxycarbonyl-piperazine(60 mg) and sodium triacetoxyborohydride (100 mg) in dry1,2-dichloroethane (12 mL) was stirred at 23° C. for 24 hours under anitrogen atmosphere. The solution was washed with a 5% sodium hydrogencarbonate solution (20 mL) and brine (20 mL). The organic layer wasdried and concentrated in vacuo to a residue, which was purified byflash chromatography (CH/AcOEt from 1:1 to 3:7) to give:

-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-[(4-tert-butoxycarbonyl)-piperazin-1-yl]-piperidine-1-carboxylic    acid [1-(R)3,5-bis-trifluoromethyl-phenyl)ethyl]-methylamide (74 mg    —T.l.c.: CH/AcOEt 1:1, Rf==0.35 hereinafter compound 1)-   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-[(4-tert-butoxycarbonyl)-piperazin-1-yl]-piperidine-1-carboxylic    acid [1-(R)3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (48    mg—T.l.c.: CH/AcOEt 1:1, Rf==0.19 hereinafter compound 2).

Trifluoroacetic acid (1 mL) was added drop-wise at 0° C. to a solutionof compound 2 (48 mg) in dry DCM (3 mL). The solution was stirred for 1hour at the same temperature and for 1 hour at r.t. Then the solvent wasremoved in vacuo and the crude dissolved in AcOEt (5 mL). The resultingsolution was washed with a saturated potassium carbonate solution anddried. After concentration in vacuo, the crude2-(R)-(4-fluoro-2-methyl-phenyl)-4-(S)-piperazin-1-yl-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (18 mg)was obtained.

Methanesulfonyl chloride (6 μL) and TEA (20 μL) were added to a solutionof this intermediate (40 mg) in anhydrous DCM (3 mL) previously cooledto 0° C. under a Nitrogen atmosphere. The solution was stirred at 0° C.for 4 hours, then it was washed with saturated sodium hydrogen carbonatesolution (5 mL). The layers were separated and the organic phase wasextracted with further DCM (3×5 mL). The combined organic extracts weredried and concentrated in vacuo to a residue, which was purified byflash chromatography (AcOEt/CH 94:6) to give the title compound (26 mg)as a colourless oil.

T.l.c.: AcOEt/CH 96:4, Rf=0.15.

NMR (d₆-DMSO): δ (ppm) 7.98 (s, 1H); 7.67 (s, 2H); 7.16 (dd, 1H); 6.89(dd, 1H); 6.74 (dt, 1H); 5.32 (q, 1H); 4.13 (dd, 1H); 3.39 (m, 1H); 3.3(m, 1H); 3.04 (m, 4H); 2.82 (s, 3H); 2.7 (s, 4H); 2.56 (m, 4H); 2.33 (s,3H); 1.9-1.4 (m, 4H); 1.45 (d, 3H).

MS (ES/+): m/z=653 [MH]⁺.

EXAMPLE 182-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(1-methanesulfonyl-piperazin-1-yl)-piperidine-1-carboxylicacid 1-[(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamideHydrochloride

A solution of example 18 (24.7 mg) in dry Et₂O (1.5 mL) was treated withhydrochloric acid (1M in Et₂O —0.042 mL) at 0° C. and the resultingmixture was stirred at 0° C. for 30 minutes. The solution wasconcentrated in vacuo and the residue was triturated with pentane togive the title compound as a white solid (22 mg).

NMR (d₆-DMSO): δ (ppm) 10.62 (bs, 1H); 7.98 (s, 1H); 7.67 (s, 2H); 7.21(dt, 1H); 6.94 (dd,

-   -   111); 6.82 (dt, 1H); 5.3 (q, 1H); 4.18 (dd, 1H); 3.8-3.45 (m,        5H); 3.3-3.1 (m, 5H); 2.99 (s,    -   311); 2.73 (s, 3H); 2.7 (t, 1H); 2.35 (s, 3H); 2.2 (m, 2H);        1.9-1.7 (m, 2H); 1.46 (d, 3H). MS (ES/+): m/z=653 [MH−HCl]⁺.

PHARMACY EXAMPLES

A. Tablets Active ingredient 10.0 mg PVP   9 mg MicrocrystallineCellulose  266 mg Sodium Starch Glycolate   12 mg Magnesium Stearate   3mg Active ingredient   50 mg PVP   9 mg Microcrystalline Cellulose  226mg Sodium Starch Glycolate   12 mg Magnesium Stearate   3 mg

The active ingredient is blended with the other excipients. The blendcan be compressed to form tablets using appropriate punches. The tabletscan be coated using conventional techniques and coatings.

B. Capsules Active ingredient 25.0 mg (1-100 mg) MicrocrystallineCellulose qs

The active ingredient is blended with microcrystalline cellulose andthen filled into suitable capsules.

C) Injection Active ingredient 2-20 mg/mL Buffer solution pH 3.5(3.0-4.0) suitable for injection qs to 10 mL (e.g. citrate buffer insterile water for injection or NaCl 0.9%)

The formulation may be packaged in glass or plastic vials or ampules.The formulation may be administered by bolus injection or infusion, e.g.after dilution with D5W or 0.9% NaCl.

The affinity of the compound of the invention for NK₁ receptor wasdetermined using the NK₁ receptor binding affinity method measuring invitro by the compounds' ability to displace [3H]—substance P (SP) fromrecombinant human NK₁ receptors expressed in Chinese Hamster Ovary (CHO)cell membranes. The affinity values are expressed as negative logarithmof the inhibition constant (Ki) of displacer ligands (pKi).

The pki values obtained as the average of at least two determinationswith representative compounds of the invention are within the range of9.80 to 10.5.

1. A compound of formula (I)

wherein R is halogen or C₁₋₄ alkyl; R₁ is hydrogen or C₁₋₄alkyl; R₂ ishydrogen, C₁₋₄alkyl; R₃ is hydrogen, C₁₋₄ alkyl; R₄ is trifluoromethyl,C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethoxy or halogen; R₅ is hydrogen,C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C(O)R₆ or S(O)₂R₆; R₆ is C₁₋₄ alkyl or C₃₋₇cycloalkyl; m is zero or an integer from 1 to 3; n is an integer from 1to 3; p is an integer from 1 to 2; X and Y are independently C(O) orCH₂; provided that i) X and Y are not both C(O) and ii) when X and Y areboth CH₂ and p is 1, R₅ is not hydrogen, C₁₋₄ alkyl or C(O)R₆—; or apharmaceutically acceptable salt or solvate thereof.
 2. A compound asclaimed in claim 1 wherein m is zero or an integer from 1 to
 2. 3. Acompound as claimed in claim 1 wherein R₁ is a methyl group.
 4. Acompound as claimed in claim 1 wherein R₂ is a hydrogen atom or a methylgroup.
 5. A compound as claimed in claim 1 wherein R₃ is a hydrogen atomor a methyl group.
 6. A compound as claimed in claim 1 wherein R₄ is atrifluoromethyl group or halogen (i.e chlorine).
 7. A compound asclaimed in claim 1 wherein R₅ is hydrogen, methyl cyclopropyl, C(O)CH₃or S(O)₂CH₃.
 8. A compound as claimed in claim 1 wherein p is
 1. 9. Acompound as claimed in claim 1 wherein R is at the 2 and/or 4 positionin the phenyl ring.
 10. A compound as claimed in claim 1 wherein n is 2and the groups R₄ are at the 3 and 5 position in the phenyl ring.
 11. Acompound as claimed in claim 1 wherein R is fluorine and/or C₁₋₄ alkyl;R₁ is a methyl group; R₂ is a hydrogen atom or a methyl group; R₃ is ahydrogen atom or a methyl group; R₄ is trifluoromethyl; R₅ is hydrogen,methyl, cyclopropyl, C(O)CH₃ or S(O)₂CH₃; m is 1 or 2; n is 2; p is 1.12. A compound selected from2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(4-methyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicacid, 1-(3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-methyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicacid, 1-(3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-methyl-3-oxo-piperazin-1-yl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(2-oxo-piperazin-1-yl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(4-Fluoro-2-methyl-phenyl)-4-(S)-(2-oxo-piperazin-1-yl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(4-Fluoro-2-methyl-phenyl)-4-(S)-(2-oxo-piperazin-1-yl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(2-oxo-4-methyl-piperazin-1-yl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-methyl-2-oxo-piperazin-1-yl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-methyl-2-oxo-piperazin-1-yl)-piperidine-1-carboxilicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(4-cyclopropyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicacid, 1-(3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(4-cyclopropyl-3-oxo-piperazin-1-yl-)-piperidine-1-carboxylicacid, 1-(3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(1-methanesulfonyl-piperazin-1-yl)-piperidine-1-carboxylicacid, 1-(3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(1-methanesulfonyl-piperazin-1-yl)-piperidine-1-carboxylicacid, 1-[(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide; andpharmaceutically acceptable salts and solvates thereof. 13-15.(canceled)
 16. A pharmaceutical composition comprising a compound asclaimed in claim 1 in a mixture with one or more pharmaceuticallyacceptable carriers or excipients.
 17. (canceled)
 18. (canceled)
 19. Amethod for the treatment of a condition mediated by a tachykinin in amammal comprising administering an effective amount of a compound asclaimed in claim
 1. 20. The method as claimed in claim 19, wherein saidtachykinin is substance P.
 21. The method as claimed in claim 19,wherein said mammal is man.
 22. A method for the treatment of a CNSdisorder in a man comprising administering an effective amount of acompound as claimed in claim
 1. 23. The method according to claim 22,wherein said CNS disorder is selected from depressive states andanxiety.
 24. A method for the treatment of emesis in a mammal comprisingadministering an effective amount of a compound as claimed in claim 1.25. A process for preparing a compound according to claim 1, wherein Xis CH₂ or C(O) and Y is CH₂, said process comprising reacting a compoundof formula (II):

with compound of formula (III):

in the presence of a suitable metal reducing agent; followed wherenecessary or desired by one or more of the following steps: i) removingany protecting group; ii) isolating the compound as a salt or a solvatethereof; or iii) separating the compound into enantiomers thereof.
 26. Aprocess for preparing a compound according to claim 1, wherein Y isC(O), said process comprising cyclizing a compound of formula (VII),

wherein P is a nitrogen protecting group and L is a suitable leavinggroup; followed where necessary or desired by one or more of thefollowing steps: i) removing any protecting group; ii) isolating thecompound as a salt or a solvate thereof; iii) separating the compoundinto enantiomers thereof.